Highly selective inhibitors of the urokinase plasminogen activator

ABSTRACT

A method is described for inhibiting urokinase plasminogen activator in a human or animal patient. The method involves administering to the patient a urokinase plasminogen activator inhibiting effective amount of a compound of the formula (I):

This application is a divisional of U.S. Ser. No. 10/239,074, filed Sep.20, 2002; now U.S. Pat. No. 6,841,702 U.S. Ser. No. 10/239,074 is a 371National Phase application of PCT/EP01/02989, filed Mar. 15, 2001.

DESCRIPTION

The present invention relates to novel highly selective inhibitors ofthe urokinase plasminogen activator (uPA, EC 3.4.21.31) of thearylguanidine type.

The urokinase-type plasminogen activator (uPA) plays a key part in tumorinvasion and formation of metastases (Schmitt et al., J. Obst. Gyn. 21(1995), 151–165) uPA is overexpressed in various types of tumor cells(Kwaan, Cancer Metastasis Rev. 11 (1992), 291–311) and binds to thetumor-associated uPA receptor (uPA-R) in which activation of plasminogento plasmin takes place. Plasmin is capable of degrading variouscomponents of the extracellular matrix (ECM) such as fibronectin,laminin and collagen type IV. It also activates some other ECM-degradingenzymes, in particular matrix metalloproteinases. High amounts oftumor-associated uPA correlate with a higher risk of metastasizing incancer patients (Stephens et al., Breast Cancer Res. & Treat. 52 (1998),99–111). Therefore, inhibition of the proteolytic activity of uPA is agood starting point for an anti-metastatic therapy.

A common feature of many known synthetic uPA inhibitors is a basicresidue containing amidino or guanidino groups, which can bind to Asp¹⁸⁹in the uPA S1 specificity pocket and which acts as an arginine mimeticthere (Spraggon et al., Structure 3 (1995), 681–691). However, most ofthe known inhibitors are not selective for uPA but also inhibit otherserine proteases such as trypsin, thrombin, plasmin or tissueplasminogen activator (tPA).

p-Aminobenzamidine is a moderately selective uPA inhibitor having aninhibition constant of 82 μM. Billstroem et al. (Int. J. Cancer 61(1995), 542–547) could show a distinct decrease in the growth rate ofDU145 tumors (a prostate adenocarcinoma cell line) in SCID mice whenadministering orally a daily dose of 125 to 250 mg ofp-aminobenzamidine/kg/day. The side effects were negligible.

Some monosubstituted phenylguanidines have proved effective andselective uPA inhibitors in vitro. These small molecules have inhibitionconstants in the micromolar range but they bind only in the S1 pocket ofuPA (Yang et al., J. Med. Chem. 33 (1990), 2956–2961). Biologicalstudies using these compounds were not carried out.

The diuretic Amiloride is a selective uPA inhibitor (Ki, uPA=7 μM) whichprevents the formation of lung metastases after i.v. inoculation of ratbreast adenocarcinoma cells (Kellen et al., Anticancer Res. 8 (1988),1373–1376). Some 3-amidinophenylalanine derivatives have likewise provedeffective inhibitors of serine proteases but these compounds generallyhave only low selectivity for uPA (Stürzebecher et al., J. Med. Chem. 40(1997), 3091–3099; Stürzebecher et al., J. Enzyme Inhib. 9 (1995),87–99).

Currently the most effective and most selective uPA inhibitors arebenzo[b]thiophene-2-carboxamidine derivatives (B428 and B623: Ki,uPA=0.32 and 0.07 μM, respectively; U.S. Pat. No. 5,340,833). Rabbani etal. (Int. J. Cancer 63 (1995), 840–845) and also Xing et al. (CancerRes. 57 (1997), 3585–3593) could show, after administration of4-iodobenzo[b]thiophene-2-carboxamidine (B428), a decrease of tumorgrowth and metastases formation in a syngeneic model of rat prostatecancer and mouse breast cancer, respectively. The latter studies showeda further decrease in primary tumor growth when B428 was administeredtogether with the antiestrogen tamoxifen.

The German patent application 199 40 389.9 proposes the use ofarylguanidine and in particular phenylguanidine derivatives as selectiveuPA inhibitors. These compounds contain a further substituent on thearomatic ring system, preferably in para position to the guanidinegroup, which substituent contains an unsubstituted or substitutedmethylene group followed by hydrogen donor/acceptor functionalities.Owing to this substitution pattern; the compounds are particularlyeffective and selective for uPA. It is assumed that these compoundsinteract as arginine mimetics with the Asp¹⁸⁹ amino acid residue in theS1 pocket of uPA and can interact with the S2 and/or S3 pockets of uPA.

Surprisingly, further aryl guanidine derivatives have now beenidentified which can interact even more specifically with uPA, inparticular with the amino acid residues Gln¹⁹² and/or Ser²¹⁴. Inaddition to the guanidine group these compounds contain anothersubstituent on the aromatic ring system, which contains an unsubstitutedor substituted methylene group followed by a hydrogen donor function, ahydrogen acceptor function and again a hydrogen donor function.

The present invention relates to the use of compounds of the formula (I)

in which

-   Ar is an aromatic or heteroaromatic ring system,-   X¹ is a radical of the formula (IIa), (IIb) or (IIc):

-   R¹ is H, an unsubstituted or substituted alkyl, alkenyl, alkynyl,    aryl or/and heteroaryl radical,-   R² is halogen, C(R³)₃), C₂ (R³) 5, OC(R³)₃ or OC₂(R³)₅,-   R³ is in each case independently H or halogen, in particular F,-   R⁴ and R⁵ are H or an unsubstituted or substituted alkyl, alkenyl or    alkynyl radical, where at least one of the radicals R⁴ and R⁵    contains a hydrogen bond donor group, for example OH, NH₂, SH, OR¹,    NHR¹, N(R¹)₂, SR¹, CO, CS,-   R⁶ and R⁷ are H or an unsubstituted or substituted alkyl, alkenyl or    alkynyl radical, where at least one of the radicals R⁶ and R⁷    contain a hydrogen bond donor group, for example OH, NH₂, SH, OR¹,    NHR¹, N(R¹)₂, SR¹, CO, CS, and where R⁴ or R⁵ may be bridged with R⁶    or R⁷,-   R⁸ is H or an unsubstituted or substituted alkyl, alkenyl, alkynyl,    aryl or/and heteroaryl radical or —SO₂—R⁹, where R⁶ may or may not    be bridged with R⁶ or R⁷,-   R⁹ is H or an unsubstituted or substituted alkyl, alkenyl, alkynyl,    aryl or/and heteroaryl radical,-   X² is a hydrogen bond acceptor group, in particular NH, NR¹⁰, O or    S,-   R¹⁰ is an unsubstituted or substituted alkyl, alkenyl or alkynyl    radical, and-   m is an integer from 0 to 4,    or salts of said compounds for preparing an agent for inhibition of    the urokinase plasminogen activator.

The compounds may be present as salts, preferably as physiologicallytolerated acid salts, for example as salts of mineral acids,particularly preferably as hydrochlorides or as salts of suitableorganic acids. The guanidinium group may carry, where appropriate,protective functions which are removable by cleavage, preferably underphysiological conditions. The compounds may be present as optically purecompounds or as mixtures of enantiomers or/and diastereoisomers.

In the compounds of the formula (I), Ar is preferably an aromatic orheteroaromatic ring system having a single ring, in particular a benzenering. In this ring system the substituents CHX¹R¹ and NHC(NH)NH₂ arepreferably arranged in meta or para position and particularly preferablyin para position. In addition, Ar may further contain other,non-hydrogen substituents R². The number of substituents R² ispreferably 0, 1, 2 or 3, particularly preferably 0 or 1 and mostpreferably 0. Preferred examples of R² are halogen atoms (F, Cl, Br orI), CH₃, CF₃, OH, OCH₃ or OCF₃.

The substituent —CHX¹R¹ is critical for inhibitor activity. R¹ may be Hor an unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or/andheteroaryl radical. The alkyl radical may be a straight-chain orbranched C₁–C₁₀-alkyl group, in particular a C₂–C₄-alkyl group or aC₃–C₈-cycloalkyl group which may be substituted with, for example,C₁–C₃-alkoxy, hydroxyl, carboxyl, amino, sulfonyl, nitro, cyano, oxoor/and halogen or else with aryl or heteroaryl radicals. Alkenyl andalkynyl radicals are preferably C₂–C₁₀ groups, in particular C₂–C₄groups which may be unsubstituted or substituted as described above.Aryl and heteroaryl radicals may be substituted, for example, withC₁–C₆-alkyl, C₁–C₃-alkoxy, hydroxyl, carboxyl, sulfonyl, nitro, cyanoor/and oxo.

The X¹ group preferably contains at least one or two substituents (R⁴ orR⁵ or/and R⁶ or R⁷), which contain a hydrogen bond donor group and alsoa substituent X² which contains a hydrogen bond acceptor group. Thehydrogen bond donor substituents contain a group which provides ahydrogen atom or/and an electron pair for a hydrogen bond. The distanceof the hydrogen bond donor group from the carbon atom to which thesubstituents 4 and R⁵ and, respectively, R⁶ and R⁷ are bound ispreferably 1 to 3 carbon atoms, particularly preferably 1 to 2 carbonatoms and most preferably 1 carbon atom. Examples of hydrogen bond donorgroups are OH, NH₂, SN, OR¹, NHR¹, N(R¹)₂, SR¹. Preferred examples ofsubstituents containing hydrogen bond donor groups are hydroxymethyl,2-hydroxyethyl, —CO₂H, —CO₂R¹, where R¹ is defined as above and ispreferably an alkyl group or an aryl group such as, for example, thebenzyl group, e.g. —CO₂CH₂—Ph, CONH₂, —CONHR¹, CONR¹, where R¹ is asdefined above, e.g. CONHCH₃, —CON(CH₃)₂, CSOH, CSOR¹, —COSH, COSR¹, COR¹and CSR¹, where R¹ is as defined above. It is also possible that twosubstituents containing hydrogen bond donor groups are bridged, forexample via a C₂–C₃ bridge. Examples of substituents bridged in this wayare 1,2-dihydroxyethylene or 1,3-dihydroxypropylene.

A substituent R⁴/R⁵ and, respectively, R⁶/R⁷ which contains no hydogenbond donor group is preferably hydrogen or an halogen-substituted or nothalogen-substituted methyl or ethyl group. A particularly preferredsubstituent of this kind is hydrogen.

The hydrogen bond acceptor substituent X² is preferably NH or O,particularly preferably O.

Furthermore, the X¹ group contains a substituent R⁸ which preferablycarries out a steric function. R⁸ may be hydrogen, an alkyl, alkenyl,alkynyl, aryl, heteroaryl, carboxyalkyl, carboxyalkenyl,carboxy-alkynyl, carboxyaryl or carboxyheteroaryl radical or —SO₂—R⁹,where R⁹ may have the same meaning as stated for R⁸. Advantageously, R⁸and R⁹ are different from hydrogen and contain at least 4, for example 6to 20, carbon atoms. R⁸ may or may not be bridged with R⁶ or R⁷.

The substituents R⁸ and R⁹ contain preferably space-filling groups whichmay be selected from the group comprising unsubstituted or substitutedaryl radicals, in particular phenyl and substituted phenyl radicals andunsubstituted or substituted branched alkyl, alkenyl or alkynylradicals, in particular with tertiary carbon atoms such as tert-butyl orneopentyl, or unsubstituted or substituted cycloalkyl radicals, inparticular bi- or tricycloalkyl radicals such as adamantyl.

The compounds of the formula (I) may be prepared, for example, startingfrom p-aminobenzylamine according to the reaction schemes shown in theGerman patent application 199 40 389.9. For example, 4-aminobenzyl-aminemay be reacted with a protective reagent for amino groups, for exampledi-tert-butyl pyrocarbonate, to give a protected intermediate,4-(N-Boc-aminomethyl)aniline, Boc meaning tert-butyloxycarbonyl. Thearomatic amino function of this compound can be reacted with aguanidinylation reagent, for example N,N′-di-Z-N″-triflylguanidine,resulting in 1-[4-(N-Boc-aminomethyl) phenyl]-2,3-di-Z-guanidine, Zbeing benzyloxycarbonyl. This compound can be converted to1-[4-(aminomethyl)phenyl]-2,3-di-Z-guanidinium hydrochloride by removingthe Boc protective group by cleavage. This compound may in turn bereacted with reactive compounds such as, for example, chloroformicesters, isocyanates or N-hydroxysuccinimide esters to give the desiredfinal products.

To prepare hydrogenation-labile compounds, 4-amino-benzylamine can bereacted with a protective reagent for amino groups, for examplebenzyloxycarbonyl-oxysuccinimide to give a protected intermediate andthen with a further guanidinylation reagent, for exampleN,N′-di-Boc-1-guanylpyrazole This compound can be hydrogenated and thenbe reacted with reactive compounds to give the desired final products.

The urokinase inhibitors of the invention may be used, whereappropriate, together with suitable pharmaceutical excipients orcarriers for producing medicaments or in diagnostics. In thisconnection, administration in combination with other active substances,for example other urokinase inhibitors such as, for example, antibodiesor/and peptides, is possible.

The medicaments may be administered in humans and animals topically,orally, rectally or parenterally, for example subcutaneously orintravenously, for example in the form of tablets, coated tablets,capsules, pellets, suppositories, solutions or transdermal systems suchas plasters.

The compounds of the invention are suitable for controlling disorderswhich are associated with pathological overexpression of uPA or/anduPAR. They are, for example, capable of very effectively inhibiting thegrowth or/and spreading of malignant tumors and also metastasizing oftumors. It is possible to use the uPA inhibitors, where appropriate,together with other tumor agents or with other types of treatment, forexample radiation or surgery. Furthermore, the inhibitors of theinvention are also effective in other uPA-associated disorders.

uPA inhibitors of the invention are preferably characterized in thatthey have a K_(i) which is at least two times, preferably at least fivetimes and particularly preferably at least 10 times and up to 1000 timeslower for uPA than for tPA. It is furthermore remarkable that thecompounds of the invention only marginally affect blood clotting, sincetheir K_(i) values are too high for effective inhibition of thrombin,plasmin and factor Xa.

The inventive substances of the formula (I) may be used in the form ofconjugates with physiologically effective substances, for exampleradiolabels or cytotoxic agents, e.g. chemotherapeutics such ascisplatin or 5-fluoruracil, or with peptides. Furthermore, it is alsopossible to incorporate the substances into the membrane of carriervesicles, for example liposomes, and thus to make possible targeting ofactive substances enclosed in said carrier vesicles, for examplecytotoxic agents such as doxorubicin.

The present invention provides a method for inhibiting urokinase inliving creatures, in particular in humans, by administering an effectivequantity of at least one compound of the formula (I). The dosing of thecompound is commonly in the range from 0.01 to 100 mg/kg of body weightper day. The length of treatment depends on the seriousness of thedisorder and may range from a single dose up to a treatment lastingseveral weeks or even several months, which may be repeated atintervals, where appropriate.

Finally, the present invention relates to novel arylguanidinederivatives of the formula (I).

The invention is intended to be illustrated in more detail by thefollowing examples and figures in which:

FIG. 1 shows examples for 5 compounds of the formula (I) of theinvention, and

FIG. 2 shows examples for further preferred compound classes of theformula (I).

EXAMPLES

Materials and Methods

All solvents and reagents used for the synthesis of uPA inhibitors wereof the highest commercially available quality and were, if necessary,further purified and dried by standard methods. Analytical HPLC wascarried out on Nucleosil 100/C18 columns (Macherey-Nagel, Düren,Germany) using a linear acetonitrile/2% H₃PO₄ gradient (from 5:95 to90:10 in 13 min). MS spectra were measured in a Perkin Elmer API 165mass spectrometer.

Example 1

Synthesis of Compounds of the Formula (I)

ST390: N-(4-guanidinobenzyl)-D,L-tropamide Hydrochloride

2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU) (23 mg; 0.07 mmol) was added to a solution of1-[4-(aminomethyl)phenyl]-2,3-di-Z-guanidine hydrochloride (30 mg; 0.064nmol), D,L-tropic acid (10.6 mg; 0.064 mmol), 1-hydroxybenzotriazole(HOBt) (10 mg; 0.07 mmol) and triethylamine (10 μl; 0.192 mmol) indichloromethane (3 ml) and the solution was stirred at room temperature.After 2 h, TBTU (15 mg; 0.047 mmol) and triethylamine (10 μl; 0.192mmol) were added once more. After another 3 h, the solution was dilutedwith 30 ml of dichloromethane, and washed 3× with 5% NaHCO₃ solution, 2×with 0.1 HCl and 1× with saturated NaCl solution. The organic phase wasdried (Na₂SO₄) and the solvent was stripped off under reduced pressure.The Z protective groups (benzyloxycarbonyl) are removed by dissolvingthe compound in methanol, stirring the solution and hydrogenating thecompound over a 10% palladium-activated carbon catalyst for 3 h. Afterremoving the catalyst by filtration, the solvent was evaporated underreduced pressure. The product was recrystallized fromisopropanol/diisopropyl ether after adding 1 equivalent of HCl indioxane.

Yield: 13 mg (58%); HPLC: tk 5.6 min; MS 313 (M+H)⁺calculated 312 forC₁₇H₂₀N₄O₂

ST399:N-[4-(2,3-bis-Bocguanidino)benzyl]2-(benzyl-oxycarbonyl)-2-phenylaceataride

TBTU (88 mg; 0.274 mmol) was added to a solution of1-[4-(aminomethyl)phenyl]-2,3-di-tert-butyloxycarbonyl-guanidinehydrochloride (8) (100 mg; 0.249 mmol), monobenzyl 2-phenylmalonate(67.3 mg; 0.249 mmol), HOBt (37 mg; 0.274 mmol) and triethylamine (104μl; 0.747 mmol) in DMF (5 ml), and the solution was stirred at roomtemperature overnight. After stripping off the solvent under reducedpressure, the residue was taken up in ethyl acetate (20 ml) and washed3× with 5% NaHCO₃ solution, 3× with 0.5 M HCl and 1× with saturated NaClsolution. The organic phase was dried (Na₂SO₄) and the solvent wasstripped off under reduced pressure. The product was recrystallized fromethanol/water.

Yield: 78 mg (51%); HPLC: t_(R) 13.0 min; MS 617 (M+H)⁺, calculated 616for C₃₄H₄₀N₄O₇

ST401: N-(4-guanidinobenzyl) 2-(benzyloxycarbonyl)-2-phenylacetamidehydrochloride

The Boc protective groups were removed by dissolving the compound ST399(12 mg; 19.5 μM) in 7 M HCl/dioxane (2 ml). After 8 h the solvent wasstripped off under reduced pressure and the product was recrystallizedfrom isopropanol/diisopropyl ether.

Yield: 4 mg (454%); HPLC: t_(R) 9.0 min; MS (M+H)⁺, calculated 416 forC₂₄H₂₄N₄O₃

ST406: N-(4-guanidinobenzyl) 2-(hydroxycarbonyl)-2-phenylacetamideHydrochloride

The benzyl group was removed from compound ST399 (150 mg; 0.244 mmol) bycatalytic hydrogenation in a solution of isopropanol (30 ml) anddichloromethane on a Pd/activated carbon catalyst. After 5 h thecatalyst was filtered off and the solvent was stripped off. Treatmentwith methyl tert-butyl ether in an ultrasound bath gave the product as alight yellow powder. Subsequently, the Boc protective groups wereremoved, as described for ST401, and the crude product was purified bypreparative HPLC.

Yield: 37 mg (42%); HPLC: t_(R) 4.6 min; MS 327 (M+H)⁺, calculated 326for C₁₇H₁₈N₄O₃

Example 2

In-Vitro Inhibition of Urokinase by Selected Compounds of the Formula(I)

The uPA inhibitor activity was determined by incubating 200 μl of Trisbuffer (0.05 mol/l, containing the inhibitor, 0.154 mol/l NaCl, 5%ethanol, pH 8.0), 25 μl of substrate (Pefachrome UK orBZ-β-Ala-Gly-Arg-pNA in H₂O; Pentapharm Ltd, Basle, Switzerland) and 50μl of sc-urokinase (Ribosepharm GmbH, Haan, Germany) or anothercorresponding protease at 25° C. After 3 min, the reaction wasinterrupted by adding 25 μl of acetic acid (50%) and absorbance at 405nm was determined by means of a microplate reader (MR 5000, Dynatech,Denkendorf, Germany). The K_(i) values were determined by linearregression according to Dixon by means of a computer program. The K_(i)values are the average of at least three determinations, and thestandard deviation was below 25%.

Owing to their structure, the compounds shown in FIGS. 1 and 2 caninteract with the active site of uPA. The results for selected compoundsof the formula (I) are listed in table 1.

TABLE 1 K₁ [μM] No. Formula uPA Plasmin FXA Thrombin Trypsin ST-390

 51 >1000 >1000 >1000 >1000 ST-401

1.4 >1000 >1000 >1000 n.t. ST-406

<10 n.t. n.t n.t n.t ST-100

<1  n.t. n.t. n.t. n.t. n.t. = not tested

1. A method of inhibiting urokinase plasminogen activator in a human oranimal patient, comprising: administering to the patient a selectiveurokinase plasminogen activator inhibiting effective amount of acompound of the formula (I):

wherein, Ar is an aromatic or heteroaromatic ring system, X¹ is aradical of the formula (IIa), (IIb) or (IIc):

R¹ is H, an unsubstituted or substituted alkyl, alkenyl, alkynyl, arylor heteroaryl radical, R² is halogen, C(R³)₃, C₂(R³)₅, OC(R³)₃ orOC₂(R³)₅, R³ is in each case independently H or halogen, R⁴ and R⁵ are Hor an unsubstituted or substituted alkyl, alkenyl or alkynyl radical,where at least one of the radicals R⁴ and R⁵ contain a hydrogen bonddonor group, where the hydrogen bond donor group provides a hydrogenatom or/and an electron pair for a hydrogen bond, R⁶ and R⁷ are H or anunsubstituted or substituted alkyl, alkenyl or alkynyl radical, where atleast one of the radicals R⁶ and R⁷ contains a hydrogen bond donorgroup, where the hydrogen bond donor group provides a hydrogen atomor/and an electron pair for a hydrogen bond and where R⁴ or R⁵ may bebridged with R⁶ or R⁷, R⁸ is H or an unsubstituted or substituted alkyl,alkenyl, alkynyl, aryl or heteroaryl radical or —SO₂—R⁹, where R⁸ may ormay not be bridged with R⁶ or R⁷, R⁹ is H or an unsubstituted orsubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl radical, X² is ahydrogen bond acceptor group, which is NH, NR¹⁰, O or S, R¹⁰ is anunsubstituted or substituted alkyl, alkenyl or alkynyl radical, and m isan integer from 0 to 4, or a salt thereof.
 2. The method of claim 1,wherein the compound is administered to the patient to treat a disorderassociated with overexpression of urokinase plasminogen activator, or areceptor for it.
 3. The method of claim 1, wherein the compound isadministered to inhibit malignant tumor growth in a patient.
 4. Themethod of claim 1, wherein the compound is administered to inhibit tumormetastasis in a patient.
 5. The method of claim 1, wherein the compoundis administered in a dose of 0.01 to 100 mg/kg of patient body weightper day.
 6. The method of claim 1, wherein the compound is administeredtogether with at least one other urokinase inhibitor.
 7. The method ofclaim 1, wherein in the compound of formula (I), Ar is a benzene ring.8. The method of claim 1, wherein in the compound of formula (I), thesubstituents —CHX¹R¹ and

are arranged on the benzene ring in para position in relation to oneanother.
 9. The method of claim 1, wherein in the compound of formula(I), for R⁴, R⁵, R⁶ and R⁷, the hydrogen bond donor groups are selectedfrom OH, OR¹, NH₂, NHR¹, N(R¹)₂, SH and SR¹.
 10. The method of claim 1,wherein in the compound of formula (I), the hydrogen bond donor group iscontained in a group selected from —CH₂OH, —CH₂CH₂OH, —CO₂H, —CO₂R¹,—CONH₂, —CONHR¹, —CON(R¹¹)₂, —COSH, —COSR¹, —CSOH, —COSR¹, —COR¹ and—CSR¹.
 11. The method of claim 1, wherein in the compound of formula(I), the hydrogen bond acceptor groups for X² are selected from O andNH.
 12. The method of claim 1, wherein in the compound of formula (I),R⁸ and R⁹ are selected from the group consisting of unsubstituted orsubstituted aryl radicals, unsubstituted or substituted tertiary alkylradicals and cycloalkyl radicals.
 13. The method of claim 1, wherein inthe compound is administered in the form of a tablet, coated tablet,capsule, pellet, suppository, solution or transdermal system.
 14. Themethod of claim 1, wherein in the compound of formula (I), R⁸ and R⁹ areselected from the group consisting of phenyl and substituted phenylradicals, unsubstituted or substituted tertiary alkyl radicals andbicycloalkyl radicals.
 15. The method of claim 1, wherein in thecompound of formula (I), R⁸ and R⁹ are selected from the groupconsisting of phenyl and substituted phenyl radicals, unsubstituted orsubstituted tertiary alkyl radicals and an adamantyl radical.